Psilocybin-Assisted Therapy: A Review of a Novel Treatment for Psychiatric Disorders

This 2017 review examines studies on psilocybin-assisted therapy to treat psychiatric disorders related to depression, anxiety, and substance abuse. In contrast to conventional paradigms, psilocybin-assisted therapy consists of only a few six-hour medication therapy sessions that may significantly improve symptoms and help patients achieve response or remission within weeks with support from integrative psychotherapy sessions.

Abstract

Review: Recent research suggests that functional connectivity changes may be involved in the pathophysiology of psychiatric disorders. Hyperconnectivity in the default mode network has been associated with psychopathology, but psychedelic serotonin agonists like psilocybin may profoundly disrupt these dysfunctional neural network circuits and provide a novel treatment for psychiatric disorders. We have reviewed the current literature to investigate the efficacy and safety of psilocybin-assisted therapy for the treatment of psychiatric disorders. There were seven clinical trials that investigated psilocybin-assisted therapy as a treatment for psychiatric disorders related to anxiety, depression, and substance use. All trials demonstrated reductions in psychiatric rating scale scores or increased response and remission rates. There were large effect sizes related to improved depression and anxiety symptoms. Psilocybin may also potentially reduce alcohol or tobacco use and increase abstinence rates in addiction, but the benefits of these two trials were less clear due to open-label study designs without statistical analysis. Psilocybin-assisted therapy efficacy and safety appear promising, but more robust clinical trials will be required to support FDA approval and identify the potential role in clinical psychiatry.”

Authors: Kelan Thomas, Benjamin Malcolm & Dan Lastra

Summary

Recent research suggests that dysfunctional neural network circuits may be involved in the pathophysiology of psychiatric disorders. Psilocybin-assisted therapy may be a promising treatment for psychiatric disorders, but more robust clinical trials are required to support FDA approval.

ARTICLE HISTORY

Keywords: anxiety, depression, psychedelic, substance use

The psychedelic compound LSD may have been one catalyst for ushering in the modern era of molecular psychiatry, since researchers first recognized the chemically similar endogenous neurotransmitter serotonin.

Advances in neuroimaging technology have enabled a more robust investigation of mental disorders than was possible in the 1950s. This has prompted the NIMH to propose a new diagnostic paradigm.

The RDoC framework consists of a matrix specifying functional constructs characterized in aggregate by the genes, molecules, and circuits used to measure human behavior. The hyperconnectivity of the subgenual-cingulate cortex in the default mode network may explain the excessive ruminating thoughts of depressed patients.

Psilocybin-assisted therapy may be a new treatment approach for psychiatric disorders, and may offer new explanations for why various treatment modalities, such as electroconvulsive therapy, transcranial magnetic stimulation, ketamine infusion, and psilocybin-assisted therapy, rapidly reduce depression symptoms.

Methods

We reviewed the available literature on psilocybin-assisted therapy for psychiatric disorders and performed a PubMed search to provide background drug information about this novel therapeutic agent.

Pharmacokinetics

Psilocybin is a substituted indolealkylamine from the tryptamine group of compounds that is rapidly dephosphorylate to an active metabolite, psilocin, in the intestinal mucosa. Psilocin is also glucuronidated by UGTs into psilocin glucuronide, which is then excreted in the urine.

Psilocybin administered intravenously (IV) had a half-life of 74 minutes, but when given by mouth (PO) had a half-life of 163 minutes. Psilocybin’s bioavailability was 52.7% after PO psilocybin administration (10 – 20 mg).

Pharmacodynamics

Psilocybin binds with the highest affinity to 5-HT2A receptors and to a lesser extent 5-HT1A receptors, and stimulates PLC, which leads to PKC activation and an increased release of Ca2+ from intracellular stores.

Psilocybin’s psychological effects are mediated primarily by agonism at the 5-HT2A receptor subtype, as evidenced by the reduction of psilocybin-induced reductions in the acoustic startle response measured by prepulse inhibition at short lead intervals.

The 5-HT2A receptor agonism may be especially significant in the cerebral cortex, where high concentrations of 5-HT2A receptors have been shown in postmortem brain tissue. This could allow cortical areas to receive more sensory information passing through.

Psilocybin has been shown to cause transient increases in blood pressure and heart rate in clinical trials, but these effects are transient and normalize six hours post-dose.

Clinical trials for cancer-related anxiety and depressive disorders

Grob et al. (2011) conducted a double-blind, placebo-controlled, crossover study with 12 participants with advanced-stage cancer and reactive anxiety. The main outcomes were cardiac safety and subjective experience, followed by Beck Depression Inventory, Profile of Mood States, and State-Trait Anxiety Inventory efficacy measures.

Psilocybin decreased anxiety and heart rate, and increased blood pressure. POMS was not significantly different from baseline at any time point during the six months.

Ross et al. (2016) conducted a double-blind, placebo-controlled, crossover study of 29 participants with cancer-related anxiety and depression. The primary outcome variables were self-reported STAI for anxiety, HADS and BDI for depression, and these were measured pre-crossover at baseline, one day pre-dose 1, one day post-dose 1, two weeks post-dose 1, six weeks postdose 1, and seven weeks postdose 1.

Participants first receiving psilocybin had lower mean scores on all six rating subscales than participants first receiving niacin (p 0.05). The largest effect size was observed for the HAD-T score, with a Cohen’s d = 1.36 (p 0.001). The depression response and remission rates were higher for participants first receiving psilocybin than the niacin placebo at seven weeks post-dose 1, and the subjective effects of the psilocybin sessions were positively correlated with the magnitude of score change for the following primary outcomes.

The most common adverse events related to psilocybin were elevations in blood pressure and heart rate, headaches, transient anxiety, nausea, and transient psychotic-like symptoms.

Griffiths et al. (2016) conducted a randomized, double-blind, crossover study with 51 cancer participants who had symptoms of depression and/or anxiety. They were given either high-dose psilocybin (22 or 30 mg/70 kg) or low-dose psilocybin (1 or 3 mg/70 kg) along with psychological support. The primary outcome variables were depression and anxiety response and remission measured by the GRID-Hamilton Depression Rating Scale and the structured interview guide for the Hamilton Anxiety Rating Scale.

Participants receiving high-dose psilocybin first showed greater response and remission rates on the GRID-HAMD-17, HAM-A, and HAD-D rating scales than participants receiving low-dose psilocybin first at five weeks post-session 1 and six months follow-up.

Adverse events were more frequent in high-dose vs. low-dose psilocybin sessions, with more participants experiencing transient elevated SBP, elevated DBP, nausea/vomiting, physical discomfort, anxiety, psychological discomfort, and paranoid ideation.

Clinical trial for treatment-resistant major depressive disorder

A pilot study of 12 participants with moderate to severe MDD who had failed at least two antidepressants was conducted. Psilocybin was administered along with psychological support and the participants were followed for several time points.

After one week, the mean QIDS was 19.2, and after three months, it was 9.2. Adverse events were reported during the psilocybin sessions, including transient anxiety, confusion or thought disorder, nausea, headache, and paranoia.

Clinical trial for obsessive-compulsive disorder

In an open-label, dose-escalation study, nine participants diagnosed with obsessive-compulsive disorder received up to four doses of psilocybin with at least a week between sessions. The participants’ symptoms of OCD were assessed before and after psilocybin ingestion.

A repeated measures ANOVA was used to analyze efficacy with YBOCS values. Psilocybin administration reduced mean YBOCS scores from 18.3 to 24.1, and then ranged from 10.7 to 11.3 hours after administration.

Clinical trial for alcohol dependence

Bogenschutz et al. (2015) conducted an open-label proof of concept study in 10 participants who met DSM-IV criteria for alcohol dependence, drank heavily at least two of the past 30 days, and were concerned about their drinking. Psilocybin was administered at a dose of 0.3 mg/kg during the first session and 0.4 mg/kg during the second session.

Psilocybin decreased heavy drinking from 35% at baseline to 9% between one to eight weeks after the first psilocybin session. Intensity of subjective psilocybin experiences was negatively correlated with percent of heavy drinking days.

Clinical trial for tobacco addiction

Johnson et al. (2014) conducted an open-label pilot study with 15 participants to assess the feasibility of a psilocybin-based intervention for treating tobacco addiction. The participants completed a 15-week smoking cessation protocol and reported self-reported, biologically supported, seven-day point prevalence abstinence at six months.

There were 12 participants who were abstinent after six months and 10 who were abstinent after 12 months. Three participants reported self-corrected relapses in the period between the psilocybin session and the six-month follow up.

Discussion

Seven studies have been conducted with a combined total of 135 participants on psilocybin-assisted therapy in psychiatry. The large effect sizes demonstrated in some of these studies warrant more robust clinical trials to ascertain psilocybin’s efficacy for specific psychiatric indications.

The use of psychotherapy before, during, and after psilocybin sessions improved symptoms more than psychotherapy alone. However, it is unclear what clinical benefit would be derived from psilocybin alone, since there were no experimental conditions omitting supportive psychotherapy.

Psilocybin-assisted therapy for depression symptoms has the strongest clinical evidence thus far, with reductions on rating scale scores of 3 – 25 points and higher response/remission rates after psilocybin sessions.

Psilocybin has been shown to reduce anxiety symptoms in four studies, with reductions in rating scale scores ranging from 6 to 30 points and higher response/remission rates.

The potential to treat substance use disorders with psilocybin has relatively weaker clinical evidence, but promising results from open-label proof-of-concept trials have prompted researchers to launch larger randomized controlled trials. The safety profile for psilocybin appears favorable, especially given the short-term exposure required for only a few sessions.

Conclusions

Psilocybin, a psychedelic 5-HT2A agonist, is beginning to demonstrate potential for treating psychiatric disorders related to anxiety, depression, and substance use. Psilocybin-assisted therapy may significantly improve symptom scores and help patients achieve response or remission within weeks.

Study details

Compounds studied
Psilocybin

Topics studied
Anxiety Addiction Depression

Study characteristics
Literature Review

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